Engineered IFNγ-loaded exosomes reprogram macrophage polarization and suppress tumor cell proliferation in vitro

Abstract

Macrophages are part of the immune system and play a complex role in the development of cancer. Tumor-associated macrophages (TAMs) exhibit dynamic plasticity between pro-tumorigenic (M2) and anti-tumorigenic (M1) phenotypes, presenting a promising therapeutic target for cancer immunotherapy. While pharmacological modulation of M2 to M1 repolarization shows therapeutic potential, current cytokine delivery strategies face critical challenges including non-specific macrophage clearance. To address these limitations, we developed an engineered exosome system (EXO-IFNγ) through efficient loading of interferon-γ (IFNγ) into THP-1 macrophage-derived exosomes. Functional investigations demonstrated that EXO-IFNγ effectively reprogrammed human peripheral blood mononuclear cells (PBMCs) derived M2 macrophages toward the M1 phenotype, exhibiting significantly superior polarization-modulating capacity compared to free IFNγ. To elucidate the therapeutic implications of phenotypic conversion, the bioactivity of conditioned medium (CM) derived from repolarized M1 macrophages was evaluated. The conditioned medium from repolarized M1 macrophages demonstrated potent tumor-suppressive activity, effectively inhibiting tumor cell growth and migration. Notably, the engineered exosomal delivery system demonstrated unique sustained payload release properties, endowing EXO-IFNγ generated CM with prolonged bioactivity compared to the CM produced by using IFNγ alone. Thus, EXO-IFNγ is a new macrophage polarization strategy to achieve good tumor cell killing effect by combining chemotherapy and immunotherapy.